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Abstract: TH-PO535

Novel Calcimimetic and Calcilytic Activity of Dietary Plant Polyphenols

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Ross, Edward A., College of Medicine, University of Central Florida, Orlando, Florida, United States
  • Bosak, Alexander J., College of Medicine, University of Central Florida, Orlando, Florida, United States
  • Gilbertson, Timothy A., College of Medicine, University of Central Florida, Orlando, Florida, United States
  • Willenberg, Bradley J., College of Medicine, University of Central Florida, Orlando, Florida, United States
  • Willenberg, Alicia R., College of Medicine, University of Central Florida, Orlando, Florida, United States
  • Dahir, Naima, College of Medicine, University of Central Florida, Orlando, Florida, United States
  • Phanstiel, Otto, College of Medicine University of Central Florida, Orlando, Florida, United States
Background

Plant-derived polyphenols have diverse medicinal effects involving multiple signaling pathways. With grapes reportedly improving human bone mass and associated with hypercalcemia in certain dogs, we hypothesized a new mechanism involving the calcium sensing receptor (CaSR): some compounds being calcilytic, others calcimimetic. We study CaSR and species-specific effects of plant-derived polyphenols in human and canine cells.

Methods

CaSR modulation by polyphenols was studied in pCMV-human-CaSR plasmid transfected human HEK293T cells and canine MDCK Type II cells using dual luciferase reporter (DLR) and Fura-2AM ratiometric calcium dye assays, respectively, for grape seed and pomace extracts (GSE, GPE) and plant-derived polyphenols cyanidin-3-sophoroside (C3S), cyanidin-3-glucoside (C3G), delphinidin-3-O-glucoside, procyanidin B2, kaempferol 3-β-D-glucopyranoside and resveratrol. DLR assays in HEK293T cells used 1μg/mL GSEs, GPEs or polyphenols over 65h. Live intracellular MDCK calcium imaging via Fura-2AM was studied over six minutes with 5μM of each polyphenolic compound in 1.0 then 3.0 mM Ca2+ media to assess calcimimetic or calcilytic activity. Cinacalcet was a positive calcimimetic control and was tested to rescue grape calcilytic activity. YM-254890 was a control for blocking the CaSR pathway.

Results

In HEK293T cells 1μg/mL GSE and GPE were calcimimetic (raising intracellular Ca2+), while the individual polyphenols C3G and C3S were calcilytic in both species. Cinacalcet inhibited the polyphenol-induced calcilytic effects. Surprisingly NPS-2143, a human calcilytic, was a calcimimetic in dogs.

Conclusion

This is the first evidence that polyphenols found in common foods affect calcium signaling by CaSR modulation and have species-specific calcimimetic or calcilytic properties. From preliminary data for grape extracts and individual polyphenolic compounds, we conclude that 1) these mechanisms explain how naturally-derived nutraceutical compounds may influence both human and canine medicine; 2) may provide the, heretofore, unexplained mechanism of lethal grape toxicity in dogs which 3) could lead to the development of antidotes that target the CaSR. In addition, elucidation of the active chemical moieties could guide therapeutic nutraceutical development for human bone mineral metabolism disorders.